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Pro-Apoptotic Role of the Human YPEL5 Gene Identified By

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Pro-Apoptotic Role of the Human YPEL5 Gene Identified By J. Microbiol. Biotechnol. (2017), 27(3), 633–643 https://doi.org/10.4014/jmb.1610.10045 Research Article Review jmb Pro-Apoptotic Role of the Human YPEL5 Gene Identified by Functional Complementation of a Yeast moh1Δ Mutation Ji Young Lee1, Do Youn Jun1, Ju Eun Park1, Gi Hyun Kwon1, Jong-Sik Kim2, and Young Ho Kim1* 1Laboratory of Immunobiology, School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea 2Department of Biological Sciences, Andong National University, Andong 36729, Republic of Korea Received: October 18, 2016 Revised: February 4, 2017 To examine the pro-apoptotic role of the human ortholog (YPEL5) of the Drosophila Yippee Accepted: February 6, 2017 protein, the cell viability of Saccharomyces cerevisiae mutant strain with deleted MOH1, the yeast ortholog, was compared with that of the wild-type (WT)-MOH1 strain after exposure to different apoptogenic stimulants, including UV irradiation, methyl methanesulfonate (MMS), First published online camptothecin (CPT), heat shock, and hyperosmotic shock. The moh1Δ mutant exhibited February 7, 2017 enhanced cell viability compared with the WT-MOH1 strain when treated with lethal UV *Corresponding author irradiation, 1.8 mM MMS, 100 μM CPT, heat shock at 50°C, or 1.2 M KCl. At the same time, the Phone: +82-53-950-5378; level of Moh1 protein was commonly up-regulated in the WT-MOH1 strain as was that of Fax: +82-53-955-5522; Ynk1 protein, which is known as a marker for DNA damage. Although the enhanced UV E-mail: [email protected] resistance of the moh1Δ mutant largely disappeared following transformation with the yeast MOH1 gene or one of the human YPEL1-YPEL5 genes, the transformant bearing pYES2- YPEL5 was more sensitive to lethal UV irradiation and its UV sensitivity was similar to that of the WT-MOH1 strain. Under these conditions, the UV irradiation-induced apoptotic events, such as FITC-Annexin V stainability, mitochondrial membrane potential (Δψm) loss, and metacaspase activation, occurred to a much lesser extent in the moh1Δ mutant compared with the WT-MOH1 strain and the mutant strain bearing pYES2-MOH1 or pYES2-YPEL5. These results demonstrate the functional conservation between yeast Moh1 and human YPEL5, and their involvement in mitochondria-dependent apoptosis induced by DNA damage. pISSN 1017-7825, eISSN 1738-8872 Copyright© 2017 by Keywords: Apoptosis, DNA damage, Drosophila Yippee, human YPEL5, metacaspase, S. cerevisiae The Korean Society for Microbiology MOH1 and Biotechnology Introduction YPEL family members and Drosophila Yippee, human YPEL1-YPEL4 shows 43.4-45.5% identity with Drosophila The Drosophila Yippee protein was initially identified, Yippee, and human YPEL5 shows 70.8% identity, indicating using the yeast two-hybrid method, as an intracellular YPEL5 among the human YPEL family members is the protein that interacts with a blood protein (hemoline) from most closely aligned with the Drosophila Yippee protein. the moth Hyalophora cecropia [1]. Since then, orthologs of Semiquantitative polymerase chain reaction revealed that the Drosophila Yippee protein have been found in a wide transcripts for YPEL3 and YPEL5 were ubiquitously range of eukaryotes, from yeast to human. During expressed in human tissues; however, those for YPEL1, comprehensive human chromosome sequence analysis, a YPEL2, and YPEL4 exhibited more restrictive expression novel gene family consisting of five members (YPEL1 patterns [2]. Immunofluorescence staining of African green through YPEL5) possessing a high homology with the monkey kidney fibroblast COS-7 cells showed that Ypel5 is Drosophila Yippee gene was identified [2]. Based on localized in the nucleus and centrosome at interphase, comparison of the overall amino acid sequences of human whereas it relocates to the spindle pole, mitotic spindle, March 2017 ⎪ Vol. 27⎪ No. 3 634 Lee et al. and midbody during the M phase [2, 3]. Interestingly, constructed by deletion of the MOH1 gene, and the WT- human YPEL3, which was described as a small unstable MOH1 strain to compare their cytotoxic sensitivity to apoptotic protein in murine myeloid cells [4], has been different apoptogenic stimulants such as UV irradiation, reported to be involved in growth suppression, causing DNA-damaging drug, heat shock, and hyperosmotic shock. cellular senescence in human cell lines, and its expression is Additionally, we have examined whether transformation regulated by the tumor suppressor protein p53, with lower of the moh1Δ mutant with recombinant plasmids bearing expression in several human tumors [5-7]. the MOH1 gene or one of the YPEL family genes can These previous observations raised the possibility that abrogate the elevated resistance of the mutant strain human YPEL family proteins play an important role in the against lethal UV irradiation, due to their pro-apoptotic regulation of cell division and/or apoptosis; however, this contribution to the mitochondrial apoptotic pathway. prediction remains to be elucidated. Furthermore, it is uncertain whether the intracellular function of YPEL family Materials and Methods proteins, which was predicted in the human orthologs, can be extended to other eukaryotic species, including yeasts. Reagents, Kits, Antibodies, Cells, and Media The budding yeast Saccharomyces cerevisiae ortholog MOH1 The camptothecin (CPT) and the DNA alkylating agent methyl gene was identified as a gene (YBL049W) possessing methanesulfonate (MMS) were purchased from Sigma-Aldrich sequence similarity to the Drosophila Yippee gene when (USA). An ECL western blot kit was purchased from GE Healthcare sequencing and functional analysis were performed for a Life Sciences (UK). The FITC-Annexin V apoptosis detection kit and JC-1 (5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolocarbocyanine 32,560 bp segment of the left arm of S. cerevisiae chromosome iodide) were purchased from Invitrogen (USA). Anti-Ynk1 (anti- II [1, 8]. Although analysis of the phenotype of S. cerevisiae NM23-H1) was purchased from Santa Cruz Biotechnology (USA), deletion mutants can be an efficient approach for studying and anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene function [9-11], there have been no reports on antibody was purchased from Thermo Scientific (USA). Rat phenotypic analysis of the mutant strain to determine antisera raised against either recombinant human YPEL5 protein MOH1 gene function. Furthermore, S. cerevisiae is a good or recombinant S. cerevisiae Moh1 protein, both of which were eukaryotic model organism for the study of many expressed as GST-fusion forms using an Escherichia coli system, fundamental biological processes, such as apoptotic cell were prepared essentially as described previously [15]. These rat death, cell cycle regulation, and DNA repair, which occur polyclonal anti-YPEL5 and anti-Moh1 antibodies were able to commonly in eukaryotic cells [12, 13]. In these contexts, we react with human YPEL5 and yeast Moh1, respectively. have decided to compare the phenotype of the moh1Δ Wild-type (WT)-MOH1 S. cerevisiae BY4741 (MATa, his3∆1, mutant strain with that of the wild-type (WT)-MOH1 leu2∆0, met15∆0, ura3∆0) and the MOH1-deletion mutant derived from S. cerevisiae BY4741 were obtained from ATCC (USA). The strain, and to determine whether the mutant phenotype WT-MOH1 strain and the moh1Δ mutant strain were cultured in can be recovered to the WT levels by complementation YPD medium containing 2% dextrose, 2% peptone, 1% yeast using plasmids expressing the human YPEL family genes. extract, and 200 μg/ml G418. The yeast strains overexpressing In a previous study, we found the human YPEL5 gene to Moh1 or YPEL1-YPEL5 were constructed by transformation of be an interesting gene, in that its mRNA expression was the yeast moh1Δ mutant with recombinant plasmid pYES2-MOH1 easily detectable in unstimulated human peripheral T cells or pYES2-YPEL1-pYES2-YPEL5. Both the WT-MOH1 strain and and then rapidly declined to undetectable level by 5 h moh1Δ mutant were transformed with empty vector plasmid following immobilized anti-CD3 activation [14]. Additionally, pYES2 and used as controls. Since the expression vector pYES2 we observed that ectopic overexpression of the YPEL5 gene contains the URA3 gene, individual transformants were selected in human cervical carcinoma HeLa cells caused a significant on synthetic complete galactose (SC-gal) solid medium (2% reduction in cell proliferation to the level of 47% of the galactose, 0.67% yeast nitrogen base w/o amino acid, 0.01% control, suggesting that YPEL5 might exert a suppressive leucine, 0.005% methionine, 0.005% histidine, 200 μg/ml G418, and 1.8% agar). effect on cell proliferation. However, the possible role of YPEL5 in induction of apoptosis, which led to the anti- Treatment Conditions for UV Irradiation, DNA-Damaging proliferative activity, and underlying cellular and molecular Drug, Heat Shock, and Hyperosmotic Shock, and Cell Viability mechanism remain to be elucidated. Assays As an attempt to obtain direct evidence for a pro-apoptotic To compare the sensitivity of the WT-MOH1 strain and the role of human YPEL5, in the present study, we have MOH1-deletion mutant with various cytotoxic factors, the cells employed a budding yeast S. cerevisiae mutant strain, grown in YPD medium at log phase were suspended in fresh YPD J. Microbiol. Biotechnol. Apoptotic Activity of Yeast Moh1 and Human YPEL5 635 medium (A600 = 0.4). Five microliters of 3-fold serial dilutions of AGTACATTTAC-3’) were used for the PCR.
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